A Hg(OTf)2-Catalyzed Enolate Umpolung Reaction Enables the Synthesis of Coumaran-3-ones and Indolin-3-ones

Article abstract of DOI:10.1021/acs.orglett.0c01096

The potential of mercury catalysis has been extended to the arena of enolate umpolung reactions for the first time by the generation of enolonium species via Hg(OTf)₂-catalyzed N-oxide addition to alkynes. The enolonium species formed can undergo intramolecular nucleophilic attack by hydroxyl or amino groups, leading to the synthesis of various coumaran-3-ones and indolin-3-ones.

Full text of DOI:10.1021/acs.orglett.0c01096

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Letter
A Hg(OTf)2‑Catalyzed Enolate Umpolung Reaction Enables the
Synthesis of Coumaran-3-ones and Indolin-3-ones
Zhouting Rong,* Weican Hu, Ning Dai, and Guoying Qian*
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ABSTRACT: The potential of mercury catalysis has been extended to the arena
of enolate umpolung reactions for the first time by the generation of enolonium
species via Hg(OTf)2-catalyzed N-oxide addition to alkynes. The enolonium
species formed can undergo intramolecular nucleophilic attack by hydroxyl or
amino groups, leading to the synthesis of various coumaran-3-ones and indolin-
3-ones.
treatment of amides with triflic anhydride, 2-I-pyridine, and
oumaran-3-ones and indolin-3-ones are valuable syn-
Cthetic targets because they are important building blocks 2,6-lutidine-N-oxide to access enolonium species A, which
proved to be a versatile intermediate for the α-functionaliza-
tion of amides.4 Szpilman and co-workers used a TMS
enolether with a hypervalent iodine to synthesize and
characterize an enolonium species B, which can serve as an
intermediate for the α-alkylation of carbonyl compounds.5
Maulide also reported the generation of enolonium C by
treating alkynes with sulfoxides in the presence of Brønsted
acid, which undergo [3,3]-sigmatropic rearrangement to yield
α-arylated ketones.6 The combined system of Brønsted acids
with pyridine N-oxides reported by Shin7 and Hashmi8 also
converted alkynes into enolonium species D (Scheme 2a).
Compared with the metal-free methods mentioned above,
transition metal-catalyzed generation of enolonium species and
umpolung reactions are less developed.9 Gold(I) complexes
are known to catalyze the addition of pyridine N-oxides to
alkynes to form α-oxo gold carbenes,10 which have been
applied to the synthesis of coumaran-3-ones and indolin-3-
ones by Ye and co-workers (Scheme 2b).11 In 2016, Zhang
and co-workers isolated and characterized an N-alkenoxypyr-
idinium salt E under their gold(I)-catalyzed conditions and
demonstrated versatile enolate umpolung reactivities of this
enolonium species (Scheme 2b).12 We envisaged that other
for the construction of various natural products and
pharmaceutical molecules.1 We envisioned that coumaran-3-
ones and indolin-3-ones could be synthesized via intra-
molecular α-etherification of o-hydroxyacetophenones or α-
amination of o-aminoacetophenones. However, traditional
methods for the α-functionalization of carbonyl compounds,
by generating enolates with strong bases to attack electrophiles,
can be ineffective because the electronegativity of oxygen and
nitrogen atoms makes them unlikely to be attacked by
nucleophilic enolates. In principle, an oxidation event is
needed to complete the cyclization.2 A less classical solution to
this issue is to reverse the polarity of the enolate by forming an
enolonium species. This enolonium species can display enolate
umpolung reactivity to behave as an electrophile, which can be
attacked by the hydroxyl or amino group in an SN2′ manner to
give our desired coumaran-3-one and indolin-3-one products
(Scheme 1).
There have been a considerable number of reports on the
generation of enolonium species.3 For example, Maulide and
co-workers developed an elegant metal-free method for the
Scheme 1. Our Design for the Synthesis of Coumaran-3-one
and Indolin-3-one
Received: March 26, 2020
https://dx.doi.org/10.1021/acs.orglett.0c01096
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

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a
Scheme 2. Precedents for the Generation of Enolonium
Species, Synthesis of Coumaran-3-one and Indolin-3-one,
and Our Work
Table 1. Optimization of the Reaction Conditions
b
entry
catalyst
ZnCl2
ZnBr2
ZnI2
CuCl
CuCl2
CuBr2
Zn(OTf)2
Cu(OTf)2
AgOAc
Hg(OTf)2
Hg(OTf)2
Hg(OTf)2
Hg(OTf)2
Hg(OTf)2
Hg(OTf)2
Hg(OTf)2
Hg(OTf)2
Hg(OTf)2
N-oxide
3a (H)
3a (H)
3a (H)
3a (H)
3a (H)
3a (H)
3a (H)
3a (H)
time (h)
yield (%)
1
2
3
4
5
6
7
8
6
24
24
24
24
48
48
48
48
1
1
1
1
1
1
1
1
1
23
0
0
0
0
0
0
0
0
64
92
45
40
90
49
50
55
53
9
3a (H)
3a (H)
10
11
12
13
14
15
16
17
18
3b (2-Cl)
3c (2-Br)
3d (3-Br)
3e (2,6-Cl2)
3f (2,6-Me2)
4a (H)
4b (Me)
4c (i-Pr)
a
Unless otherwise noted, all reactions were performed with 1a (0.2
mmol), catalyst (0.01 mmol), and N-oxide (0.24 mmol) in CH2Cl2 (1
b
mL) at 23 °C. The yield of 2a was determined by NMR with 1,3,5-
trimethylbenzene as the internal standard.
halides or copper halides were employed (entries 2−6). After
Zn(OTf)2, Cu(OTf)2, and AgOAc failed to give any desired
coumaran-3-one 2a, we turned our attention to Hg(OTf)2,13
an efficient inexpensive catalyst for alkyne activation, which
successfully afforded 2a in 64% yield (entry 9). We also
examined a variety of N-oxides and found that Cl-substituted
pyridine N-oxides 3b and 3e outperformed other N-oxides
with 2-Cl-pyridine N-oxide 3b giving the best yield (entries
10−17). The superiority of Cl-substituted pyridine N-oxides is
presumably due to the nucleophilicity being stronger than
those of other pyridine N-oxides, which accelerates the
addition to the alkyne. It is noteworthy that our trans-
formations can be completed in the absence of any Brønsted
acid additive, which is usually essential in gold catalysis
involving addition of N-oxide to alkynes.
With the optimal conditions in hand, we started to explore
the substrate scope of this transformation, and a variety of 2-
ethynylphenols were employed. In general, this reaction
showed good functional group tolerance, and the results are
listed in Scheme 3. 2-Ethynylphenols 1b−f bearing electron-
donating substituents such as Me and OMe at different
positions of the phenyl rings proved to be suitable substrates
for producing the corresponding coumaran-3-ones 2b−f in
good yields. Fluoro-, chloro-, and nitro-substituted coumaran-
3-ones 2g−k can also be obtained under our standard
conditions in excellent yields. 2-Ethynylnaphthol 1l reacted
smoothly to furnish dihydronaphthofuran-1-one 2l in 92%
yield. To our delight, when the reaction of 1a was carried out
on a 10 mmol scale, the desired product 2a can be isolated in
90% yield, which indicated that our conditions were robust for
large-scale preparations.
metals that are more affordable than gold, as long as they could
promote the addition of N-oxide to alkynes, could also catalyze
the formation of N-alkenoxypyridinium species, which could
serve as versatile intermediates for the synthesis of α-
functionalized ketones. Herein, we report the first Hg(OTf)2-
catalyzed enolate umpolung reaction that enables the synthesis
of various coumaran-3-ones and indolin-3-ones.
At the outset, we used commercially available 2-ethynyl-
phenol 1a as the substrate to screen conditions, and the results
are summarized in Table 1. Upon exposing 1a to 5 mol %
ZnCl2 in the presence of pyridine N-oxide (1.2 equiv) in
dichloromethane at room temperature, we were able to isolate
our desired product 2a, albeit in low yield (entry 1). Then, we
continued to test other inexpensive transition metal salts, but
to our disappointment, no reaction took place when other zinc
B
https://dx.doi.org/10.1021/acs.orglett.0c01096
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Letter
a
can also be tolerated, and indolin-3-ones 6e−i were obtained
in 73−84% yields.
Scheme 3. Substrate Scope of Coumaran-3-one Synthesis
Then, we turned our attention to the reaction of
disubstituted alkynes. Substrates 7a−c were synthesized, but
unfortunately, the desired 2-substituted coumaran-3-ones and
indolin-3-ones 8 were not obtained. Instead, fast consumption
of starting materials was observed in all cases, leading to the
formation of 2-substituted benzofurans and indoles 8a′−c′ in
good yields (Scheme 5).
Scheme 5. Reaction of Disubstituted Alkynes under
Standard Conditions
There is rational doubt about the mechanism of these
transformations in terms of whether α-oxo mercury carbene F
has formed during the catalytic process because the formation
of α-oxo gold carbenes has frequently been found after alkynes
are treated with N-oxides and gold(I) catalysts.14 However,
when phenylacetylene was treated with our standard
conditions in the presence of trans-stilbene or cis-stilbene, no
desired cyclopropane products 9 were detected (Scheme 6, eq
a
All reactions were performed with 1 (0.5 mmol), Hg(OTf)2 (0.025
mmol), and 2-Cl-pyridine N-oxide (0.6 mmol) in CH2Cl2 (2.5 mL) at
23 °C for 1 h. Isolated yields of 2 are listed. Ten millimoles of 1a was
employed.
b
Next, we focused on the synthesis of indolin-3-ones under
our standard conditions. Due to the fact that 2-ethynylaniline
failed to afford the desired indolin-3-one, we decided to
employ tosyl-substituted 2-ethynylaniline 5a, as it can be more
easily deprotonated under the reaction conditions, increasing
its nucleophilicity. The reaction of substrate 5a proceeded well
to give N-Ts-indolin-3-one 6a in 85% yield, with a slightly
higher Hg(OTf)2 loading (10 mol %) and a longer reaction
time (3 h). Then various N-Ts-2-ethynylanilines were
examined under these conditions, and the results are listed
in Scheme 4. Similar to the synthesis of coumaran-3-ones, the
synthesis of indolin-3-ones featured good functional group
tolerance. Substrates 5b−d bearing Me and OMe groups
afforded the corresponding indolin-3-one products 6b−d,
respectively, in excellent yields. Halogen atoms and CO2Me
Scheme 6. Attempts to Trap Potential α-Oxo Mercury
Carbene
a
Scheme 4. Substrate Scope of Indolin-3-one Synthesis
1). The intramolecular trapping of the potential mercury
carbene was performed by exposing 10 to our standard
conditions, but the expected cyclopropane product 11 could
not be found (Scheme 6, eq 2). These results led us to propose
a mechanism for our reactions without the formation of
mercury carbene. With 1a as an example, the alkynyl moiety
can be activated by Hg(OTf)2 and the addition of 2-Cl-
pyridine N-oxide takes place to give intermediate G. Intra-
molecular proton transfer leads to the protodemercurization of
intermediate G to generate enolonium species H. Then an
intramolecular SN2′ reaction occurs, which affords coumaran-
3-one 2a (Scheme 7).
In conclusion, we have demonstrated the first mercury-
catalyzed enolate umpolung reaction that allows the efficient
construction of various coumaran-3-ones and indolin-3-ones.
This method features high yields and excellent functional
group tolerance. Obviously, the formation of enolonium
intermediates by mercury catalysis has the potential to be a
a
All reactions were performed with 5 (0.5 mmol), Hg(OTf)2 (0.05
mmol), and 2-Cl-pyridine N-oxide (0.6 mmol) in CH2Cl2 (2.5 mL) at
23 °C for 3 h. Isolated yields of 6 are listed.
C
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ASSOCIATED CONTENT
* Supporting Information
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The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c01096.
Detailed experimental procedures, compound character-
ization data, and NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
Zhouting Rong − College of Biological and Environmental
Sciences, Zhejiang Wanli University, Ningbo 315100, People’s
Republic of China; orcid.org/0000-0001-7811-4890;
Email: zrong@zwu.edu.cn
Guoying Qian − College of Biological and Environmental
Sciences, Zhejiang Wanli University, Ningbo 315100, People’s
Republic of China; Email: qiangy@zwu.edu.cn
(4) (a) Gonca̧ lves, C. R.; Lemmerer, M.; Teskey, C. J.; Adler, P.;
́
Kaiser, D.; Maryasin, B.; Gonzalez, L.; Maulide, N. Unified Approach
to the Chemoselective α-Functionalization of Amides with Heter-
oatom Nucleophiles. J. Am. Chem. Soc. 2019, 141, 18437. (b) Kaiser,
D.; de la Torre, A.; Shaaban, S.; Maulide, N. Metal-Free Formal
Oxidative C−C Coupling by In Situ Generation of an Enolonium
Species. Angew. Chem., Int. Ed. 2017, 56, 5921. (c) Kaiser, D.; Teskey,
C. J.; Adler, P.; Maulide, N. Chemoselective Intermolecular Cross-
Enolate-Type Coupling of Amides. J. Am. Chem. Soc. 2017, 139,
16040.
Authors
Weican Hu − College of Biological and Environmental Sciences,
Zhejiang Wanli University, Ningbo 315100, People’s Republic
of China
Ning Dai − College of Biological and Environmental Sciences,
Zhejiang Wanli University, Ningbo 315100, People’s Republic
of China
(5) Arava, S.; Kumar, J. N.; Maksymenko, S.; Iron, M. A.; Parida, K.
N.; Fristrup, P.; Szpilman, A. M. Enolonium Species−Umpoled
Enolates. Angew. Chem., Int. Ed. 2017, 56, 2599.
(6) (a) Pons, A.; Michalland, J.; Zawodny, W.; Chen, Y.; Tona, V.;
Maulide, N. Vinyl Cation Stabilization by Silicon Enables a Formal
Metal-Free α-Arylation of Alkyl Ketones. Angew. Chem., Int. Ed. 2019,
58, 17303. (b) Kaldre, D.; Klose, I.; Maulide, N. Stereodivergent
Synthesis of 1,4-Dicarbonyls by Traceless Charge−Accelerated
Sulfonium Rearrangement. Science 2018, 361, 664. (c) Kaldre, D.;
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c01096
Notes
The authors declare no competing financial interest.
́
Maryasin, B.; Kaiser, D.; Gajsek, O.; Gonzalez, L.; Maulide, N. An
Asymmetric Redox Arylation: Chirality Transfer from Sulfur to
Carbon through a Sulfonium [3,3]-Sigmatropic Rearrangement.
Angew. Chem., Int. Ed. 2017, 56, 2212. (d) Kaiser, D.; Veiros, L. F.;
Maulide, N. Brønsted Acid-Mediated Hydrative Arylation of
Unactivated Alkynes. Chem. - Eur. J. 2016, 22, 4727. (e) Peng, B.;
Huang, X.; Xie, L.-G.; Maulide, N. A Brønsted Acid Catalyzed Redox
Arylation. Angew. Chem., Int. Ed. 2014, 53, 8718.
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Hoang, T.; Shin, S. Brønsted Acid Catalyzed Oxygenative Bimolecular
Friedel−Crafts-type Coupling of Ynamides. Angew. Chem., Int. Ed.
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(8) Graf, K.; Ruhl, C. L.; Rudolph, M.; Rominger, F.; Hashmi, A. S.
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ACKNOWLEDGMENTS
■
This work was supported by the Scientific Research Fund of
Zhejiang Provincial Education Department, the Natural
Science Foundation of Ningbo (2019A610193), and the
Zhejiang Provincial Top Key Discipline of Bioengineering
(CX2019003).
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